Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model

Abstract

Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23-32weeks) received a loading dose of morphine (50-100μg/kg), followed by a continuous infusion (5-10μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.

Keywords: Modelling; Morphine; Morphine-6-glucuronide; Pharmacokinetics/pharmacodynamics; Preterm neonates; Systematic model comparison.

Figure 1

Flowchart for the entire modelling analysis. The top part (red and blue) shows the step for the literature model comparison (as described in section 2.2.2). The green part shows the step for development of a pharmacokinetic meta model (as described in section 2.2.3), and the black part shows the step for the pharmacodynamic data analysis (as described in section 2.2.4)

Figure 2

Distribution of NPDEs (histogram) with theoretical N(0,1) distribution (dashed line) for morphine predictions. (*) indicates that the NPDEs are different from N(0,1) distribution for the specified test on a 95% significance level. A) Model 1 Anand et al., B) Model 2 Wang et al., C) Model 3 Wang et al., D) Model 4 Bouwmeester et al., E) Model 5 Knibbe et al.

Figure 3

Distribution of NPDEs (histogram) with theoretical N(0,1) distribution (dashed line) for metabolite predictions. (*) indicates that the NPDEs are different from N(0,1) distribution for the specified test on a 95% significance level. A) Model 3 Wang et al. M3G, B) Model 4 Bouwmeester et al. M3G, C) Model 4 Bouwmeester et al. M6G, D) Model 5 Knibbe et al. M3G, E) Model 5 Knibbe et al. M6G.

Figure 4

Structural pharmacokinetic meta-model of morphine (MOR) and its metabolites (M3G, M6G). The blue colour denotes components from the morphine literature model, and the red colour denotes components from the metabolite literature model. All parameter estimates was updated accordingly to the description in section 2.2.3.1 and 3.3.2. C_MOR, C_M3G, C_M6G: concentrations in compartments. CL_MOR: total morphine clearance. CLF_M3G, CLF_M6G: metabolite formation clearance. CLE_M3G, CLE_M6G: metabolite elimination clearance. F_met: metabolite formation fraction. R_in: infusion rate. V_MOR, V_M3G, V_M6G: volume of distribution.

Figure 5

Diagnostic plots for the final pharmacokinetic meta-model. The black solid lines are identity lines with a slope of 1 for plots A) and B) and a slope of 0 for plots C) and D). The black dashed lines are regression lines for the data. The red symbols represent morphine, green is M3G, and blue is M6G. Plots: A) Observed concentrations (OBS) versus population predicted concentrations (PRED). B) Observed concentrations (OBS) versus individual predicted concentrations (IPRED). C) Conditional weighted residuals (CWRES) versus time. D) Conditional weighted residuals (CWRES) versus population predicted concentrations (PRED).

Figure 6

A: Visual Predictive Check of the final meta-model of morphine and metabolite PK. The observed data are represented by blue symbols, a red solid line (median), and red dashed lines (5^th and 95^th percentiles). The red shaded area represents the 95% empirical confidence interval around the predicted median (black solid line), and the blue shaded areas represents the 95% empirical confidence interval around the 5^th and 95^th percentiles (black solid lines) of the predictions. Data were binned into 10 groups. B: Distribution of NPDEs (histogram) with theoretical N(0,1) distribution (dashed line) for the final pharmacokinetic meta-model.

Figure 7

Visual Predictive Check of PD model for PIPP score. The observed data are represented by blue symbols, a red solid line (median), and red dashed lines (5^th and 95^th percentiles). The red shaded area represents the 95% empirical confidence interval around the predicted median (black solid line), and the blue shaded areas represents the 95% empirical confidence interval around the 5^th and 95^th percentiles (black solid lines) of the predictions.